The long-term goals of this project are to elucidate the virological and immunological mechanisms of HIV-1 induced thymus depletion and to identify novel viral and host targets for interventions in pediatric AIDS therapy. It has become increasingly clear that the thymus serves as an early site for HIV-1 replication and its destruction by HIV-1 in pediatric patients correlates with accelerated disease progression. Little is known, however, about the HIV-1 pathogenesis process in the human thymus, due to the obvious difficult of studying human organs. We have used human fetal thymus and fetal liver fragments engrafted in the severe combined immunodeficiency mouse (SCID-hu Thy/Liv) and human fetal thymus organ culture (HF-TOC) model systems to study HIV-1 pathogenesis in the human thymus. Based on published as well as on my preliminary results, I hypothesize that HIV-1 infection leads to thymus destruction by induction of thymocyte activation and cell death in a paracrine fashion. The SCID-hu Thy/Liv model, the HF-TOC model and human thymocyte cell lines will be employed to define and investigate the viral pathogenic factors and the paracrine "virulence" factors. The specific aims are: 1). To define the HIV-1 pathogenic factors which induce thymocyte depletion in the human thymus and 2). To determine the mechanisms of the "pathogenic factors" mediating HIV-1 pathogenesis. The combination of viral genetics, animal and organ culture models and molecular biology will yield a wealth of information in the next 5 year. The findings will open novel avenues in development of clinical prognostic evaluation, live attenuated HIV-1 vaccines, therapeutic interventions, as well as in basic understanding of the HIV-1 pathogenesis process. It is possible that these findings will be most pertinent to the evaluation of HIV-1 disease in children, whose thymus is known to be physiologically active. Given the paucity of information about the function of the thymus in the (HIV+ or HIV-) adult, it remains unclear how they may related to adult HIV disease. Data obtained from the unique experimental systems (SCID-hu mice and HF-TOC) and development of the novel approaches (transgenic human thymus and SPAT assays) will also shed light on understanding intrathymic human T cell development and on discovery of important cytokines and receptors.